Worms' nervous system shown to alert immune system in Stanford studies

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Worms' nervous system shown to alert immune system in Stanford studies

http://www.eurekalert.org/pub_releases/2008-10/sumc-wns101008.php

The nervous system and the immune system have something in common.

Each has evolved to react quickly to environmental cues. Because the

nervous system is able to detect some of these cues - say, a

characteristic odor signaling a pathogen's presence - at a distance,

it sometimes can sense trouble earlier than the immune system, which

has to wait until the pathogen invades the organism.

So it makes sense that the two systems might talk to one another.

Stanford University School of Medicine geneticists have shown that,

indeed, they do.

In a study to be published online Oct. 14 by the journal Nature

Immunology, Man-Wah Tan, PhD, assistant professor of genetics and of

microbiology and immunology, and postdoctoral scholar Trupti Kawli

have shown that a change in the secretion patterns of nerve cells in

the minuscule soil-dwelling worm, Caenorhabditis elegans, induces a

change in the worm's susceptibility to a bacterial pathogen,

Pseudomonas aeruginosa. In humans, P. aeruginosa is an important

pathogen among cystic fibrosis patients and can cause pneumonia.

Importantly, the Stanford investigators have nailed down the

connection between the two systems. They identified a particular

molecule that, secreted by nerve cells, binds to receptors in the

worm's gut cells. When the levels of the secreted molecule fall, this

sets off a complicated chain reaction that activates the powerful

immune defense against bacterial infection. Since bacteria are what

C. elegans mainly eats, this is a handy defense to have.

The notion of crosstalk between our nervous and immune systems is

hardly surprising, said Tan. " A person who is undergoing prolonged

psychological stress - say, because they're taking care of someone

who is sick - is more likely to have reactivation of a latent

infection or become more susceptible to new ones, " he said. " That

stressful situation cannot be changed. But by identifying the

pathways through which the nervous system alters immune function in

this simple creature C. elegans, we can perhaps start to think about

how we can intervene in humans. "

The very complexity of the nervous and immune systems would make any

interactions between them exceedingly tough to tease out in humans.

So Kawli and Tan used C. elegans, because both its nervous and immune

systems have been entirely mapped out. This enabled the researchers

to manipulate the former, then watch what happened to the latter.

C. elegans has nerve cells that ordinarily secrete bioactive

molecules contained within tiny membrane-wrapped bundles, called

dense-core vesicles. The rate at which these molecules are secreted

is governed by the activity of the nervous system. One of those

secreted bioactive molecules is called ins-7. The Stanford team

obtained or generated various C. elegans mutants that lacked the

ability either to produce or to secrete ins-7, or secreted it

excessively.

By using these and other advanced laboratory tools to manipulate the

worm's ability to secrete ins-7, the researchers were able to

correspondingly alter the readiness of the minuscule creature's

innate immune system: a primitive but potent piece of the immune

system shared by C. elegans and higher organisms including humans.

People often associate " immune response " with antibodies and roving T-

cells dispatched to combat a particular viral or bacterial infection -

the so-called adaptive immune response. But that response takes a

week or two to develop, said Tan. In contrast, all of our cells have

receptors that can recognize molecular patterns common to whole

classes of pathogens (for example, characteristic viral DNA snippets,

or bacterial cell-wall constituents), immediately triggering cascades

of intracellular reactions, such as the activation of batteries of

genes that code for antimicrobial proteins.

Both the innate and adaptive branches of the immune system have to

function optimally in order for us to leave a healthy life. " The

innate immune system is our first line of defense, " said Tan. " If not

for the innate immune system, we'd be dead by the time the adaptive

immune system raises antibodies to a pathogenic invader we have not

encountered before. "

It is still a matter of speculation as to how crosstalk between the

nervous and immune systems of humans regulates innate immune

responses. But now that a clear pathway has been identified in the

worm, it will be easier to conduct focused research on higher

organisms to see if the phenomenon is universal, Tan said.

Tan acknowledged that it has not yet been proven that the signaling

of the nervous system to the immune system of C. elegans, as shown in

this experiment, occurs in nature. But there's very good reason to

believe it does.

In a separate paper set to be published online on Oct. 17 by another

journal, PLoS-Pathogens, Tan and other Stanford associates

demonstrate that P. aeruginosa - which is often isolated from the

same soil samples in which C. elegans is found and, presumably, co-

evolved with C. elegans - has a way of subverting this defense

against it. The pathogen induces excess production of ins-7 by the

worm to dull its immune responsiveness. In contrast, other human

bacterial pathogens such as Salmonella typhimurium and Enterococcus

fecalis have no such capability. Nor do abiotic stresses, such as

heat or heavy metals.

This suggests to Tan that the fine-tuning of the innate immune

response by the nervous system is effective enough in the natural

state that some pathogens with which C. elegans coexists have evolved

strategies to subvert this system.

An inducible immune response makes more sense - in worms and people -

than a state of constantly hyper-elevated immune vigilance. People

with hyperactive immune systems suffer from autoimmune and

inflammatory conditions. Although worms with downregulated secretion

from dense-core vesicles are better at combating infection, they

don't move well, which would probably prove lethal in the wild. One

of the ins-7-deficient C. elegans mutants used in the Nature

Immunology study is called unc, said Kawli, the paper's first

author. " That stands for 'uncoordinated,' " she said.

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Funding for the Nature Immunology study came from the National

Institutes of Health.

Stanford University Medical Center integrates research, medical

education and patient care at its three institutions — Stanford

University School of Medicine, Stanford Hospital & Clinics and Lucile

Packard Children's Hospital at Stanford. For more information, please

visit the Web site of the medical center's Office of Communication &

Public Affairs at http://mednews.stanford.edu.